Trelstar Drug Information

is indicated for the treatment of advanced prostate cancer. TRELSTAR is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of advanced prostate cancer.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of the three TRELSTAR formulations was evaluated in clinical trials involving patients with advanced prostate cancer. Mean testosterone levels increased above baseline during the first week following the initial injection, declining thereafter to baseline levels or below by the end of the second week of treatment.

The transient increase in testosterone levels may be associated with temporary worsening of disease signs and symptoms, including bone pain, neuropathy, hematuria, and urethral or bladder outlet obstruction. Spinal cord compression with weakness or paralysis of the lower extremities have occurred. Adverse reactions reported for each of the three TRELSTAR formulations in the clinical trials, are presented in Table 2, Table 3, and Table 4. The majority of adverse reactions related to TRELSTAR are a result of its pharmacological action, i.e., the induced variation in serum testosterone levels, either an increase in testosterone at the initiation of treatment, or a decrease in testosterone once castration is achieved.

Local reactions at the injection site or allergic reactions may occur. The following adverse reactions were reported to have a possible or probable relationship to therapy as described by the treating physician in at least 1% of patients receiving TRELSTAR 3.75 mg. Table 2. TRELSTAR 3.75 mg: Treatment-Related Adverse Reactions Reported by 1% or More of Patients During Treatment Adverse Reaction s * TRELSTAR 3.75 mg N = 140 N % Application Site Disorders Injection site pain 5

Body as a Whole Hot flush 82 58.6 Pain 3 2.1 Leg

pain 3

Fatigue 3 2.1 Cardiovascular Disorders Hypertension 5 3.6 Central and Peripheral Nervous

System Disorders Headache 7

Dizziness 2 1.4 Gastrointestinal Disorders Diarrhea 2 1.4 Vomiting 3 2.1 Musculoskeletal

System Disorders Skeletal pain 17

Psychiatric Disorders Insomnia 3 2.1 Impotence 10 7.1 Emotional lability 2 1.4

Red Blood Cell Disorders Anemia 2

Skin and Appendages Disorders Pruritus 2 1.4 Urinary System Disorders Urinary tract

infection 2

Urinary retention 2 1.4 * Adverse reactions for

TRELSTAR 3.75 mg are coded using the WHO Adverse Reactions Terminology (WHOART) The following adverse reactions were reported to have a possible or probable relationship to therapy as described by the treating physician in at least 1% of patients receiving TRELSTAR 11.25 mg. Table 3. TRELSTAR 11.25 mg: Treatment-Related Adverse Reactions Reported by 1% or More of Patients During Treatment Adverse Reactions * TRELSTAR 11.25 mg N = 174 N % Application Site Injection site pain 7

Body as a Whole Hot flush 127 73.0 Leg pain 9 5.2

Pain 6

Back pain 5 2.9 Fatigue 4 2.3 Chest pain 3 1.7 Asthenia

2

Central and Peripheral Nervous System Disorders Headache 12 6.9 Dizziness 5 2.9

Leg cramps 3

Liver and Biliary System Abnormal hepatic function 2 1.1 Metabolic and Nutritional

Disorders Edema in legs 11

Increased alkaline phosphatase 3 1.7 Musculoskeletal System Disorders Skeletal pain 23 13.2

Arthralgia 4

Myalgia 2 1.1 Psychiatric Disorders Decreased libido 4 2.3 Impotence 4 2.3

Insomnia 3

Anorexia 3 1.7 Respiratory System Disorders Coughing 3 1.7 Dyspnea 2 1.1

Pharyngitis 2

Skin and Appendages Rash 3 1.7 Urinary System Disorders Dysuria 8 4.6

Urinary retention 2

Vision Disorders Eye pain 2 1.1 Conjunctivitis 2 1.1 * Adverse reactions

for TRELSTAR 11.25 mg are coded using the WHO Adverse Reactions Terminology (WHOART) The following adverse reactions occurred in at least 5% of patients receiving TRELSTAR 22.5 mg. The table includes all reactions whether or not they were ascribed to TRELSTAR by the treating physician. The table also includes the incidence of these adverse reactions that were considered by the treating physician to have a reasonable causal relationship or for which the relationship could not be assessed.

Table 4. TRELSTAR 22.5 mg: Adverse Reactions Reported by 5% or More of Patients During Treatment Adverse Reactions * TRELSTAR 22.5 mg N = 120 Treatment-Emergent Treatment-Related N % N % General Disorders and Administration Site Conditions Edema peripheral 6 5.0 0 0 Infections and Infestations Influenza 19 15.8 0 0 Bronchitis 6 5.0 0 0 Endocrine Diabetes Mellitus/Hyperglycemia 6 5.0 0 0 Musculoskeletal and Connective Tissue Disorders Back pain 13 10.8 1

Arthralgia 9 7.5 1 0.8 Pain in extremity 9 7.5 1 0.8

Nervous System Disorders Headache 9 7.5 2

Psychiatric Disorders Insomnia 6 5.0 1 0.8 Renal and Urinary Disorders Urinary

tract infection 14 11.6 0 0 Urinary retention 6 5.0 0 0 Reproductive System and Breast Disorders Erectile dysfunction 12 10.0 12

Testicular atrophy 9 7.5 9 7.5 Vascular Disorders Hot flush 87 72.5

86

Hypertension 17 14.2 1 0.8 * Adverse reactions for

TRELSTAR 22.5 mg are coded using the Medical Dictionary for Regulatory Activities (MedDRA) Changes in Laboratory Values During Treatment The following abnormalities in laboratory values not present at baseline were observed in 10% or more of patients: TRELSTAR 3.75 mg : There were no clinically meaningful changes in laboratory values detected during therapy. TRELSTAR 11.25 mg : Decreased hemoglobin and RBC count and increased glucose, BUN, SGOT, SGPT, and alkaline phosphatase at the Day 253 visit. TRELSTAR 22.5 mg : Decreased hemoglobin and increased glucose and hepatic transaminases were detected during the study.

The majority of the changes were mild to moderate.

Post-marketing Experience

The following adverse reactions have been identified during post approval use of gonadotropin releasing hormone agonists. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Pituitary Apoplexy – During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists.

In majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

Cardiovascular System – cerebrovascular accident, myocardial infarction, pulmonary emboli, thromboembolic events (including deep venous thrombosis, transient ischemic attack, and thrombophlebitis) Central/Peripheral Nervous System – convulsions Hepatobiliary Disorder – non-alcoholic fatty liver disease Respiratory, Thoracic, and Mediastinal Disorder – interstitial lung disease Skin and Subcutaneous Tissue Disorders – SJS/TEN, DRESS, AGEP, dermatitis exfoliative, bullous dermatitis, and erythema multiforme.

No drug-drug interaction studies involving TRELSTAR have been conducted. Human pharmacokinetic data with triptorelin suggest that C-terminal fragments produced by tissue degradation are either degraded completely within tissues, are rapidly degraded further in plasma, or cleared by the kidneys. Therefore, hepatic microsomal enzymes are unlikely to be involved in triptorelin metabolism.

However, in the absence of relevant data and as a precaution, hyperprolactinemic drugs should not be used concomitantly with TRELSTAR since hyperprolactinemia reduces the number of pituitary GnRH receptors.

Pregnancy Risk Summary Based on findings in animal studies and mechanism of action, TRELSTAR can cause fetal harm when administered to a pregnant woman . Expected hormonal changes that occur with TRELSTAR treatment increase the risk for pregnancy loss. In animal developmental and reproductive toxicology studies, daily administration of triptorelin to pregnant rats during the period of organogenesis caused maternal toxicity and embryo-fetal toxicities, including loss of pregnancy, at doses as low as 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus.

Data Animal Data Studies in pregnant rats administered triptorelin at doses of 2, 10, and 100 mcg/kg/day (approximately equivalent to 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area) during the period of organogenesis demonstrated maternal toxicity and embryo-fetal toxicities. Embryo-fetal toxicities consisted of pre-implantation loss, increased resorption, and reduced mean number of viable fetuses at the high dose. Teratogenic effects were not observed in viable fetuses in rats or mice.

Doses administered to mice were 2, 20, and 200 mcg/kg/day (approximately equivalent to 0.1, 0.7, and 7 times the estimated human daily dose based on body surface area).

Pediatric Use The safety and effectiveness of TRELSTAR in pediatric patients have not been established.

Hypersensitivity

TRELSTAR is contraindicated in individuals with a known hypersensitivity to triptorelin or any other component of the product, or other GnRH agonists or GnRH.